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Introduction: In recent years, chronic lymphocytic leukemia (CLL) treatment has changed dramatically. Chemoimmunotherapy with fludarabine/cladribine, cyclophosphamide and rituximab have been almost completely replaced by targeted therapies with small molecules such as Bruton's tyrosine kinase inhibitors or B-cell lymphoma 2 (BCL-2) antagonists. However, few studies have assessed the impact of novel therapies on patient quality of life (QoL)., Areas Covered: This article reviews the safety profile of new therapeutic options and their impact on the QoL of CLL patients. The MEDLINE database was searched for English language publications from 2010 through June 2024, including the Proceedings of the American Society of Hematology from over the past five years., Expert Opinion: CLL is a clinically-heterogenous disease predominantly affecting elderly patients. The variable clinical course of disease requires personalization and individualized treatment to achieve the optimal survival outcome and acceptable safety profile, especially in the case of poor prognosis. Clinical trials performed in the past decade indicate that novel drugs, used as a single agent or as part of a conventional chemotherapy, offer promise in minimalizing relapse rates, and may allow more effective and safer treatment options by reducing the risk of adverse events, especially cytopenias and infections.

Background: Bruton's tyrosine kinase inhibitors (BTKis) are targeted treatments for B-cell tumors but have significant side effects. This study assesses and contrasts the side effects of BTKis alone and its four combination therapies., Research Design and Methods: The reporting odds ratio (ROR) was used to analyze the data on three BTKis monotherapies and combinations of ibrutinib with rituximab, obinutuzumab, venetoclax, and lenalidomide in the FDA Adverse Event Reporting System (FAERS) database up to December 2022., Results: We analyzed the top 20 PTs for each treatment regimen. In monotherapies, atrial fibrillation (ROR (95% CI): 9.88 (9.47-10.32)) in zanubrutinib and rash (6.97 (5.42-8.98)) in acalabrutinib had higher associations. In combinations, infection (6.86 (6.11-7.70)), atrial fibrillation (27.96 (22.61-34.58)) and myelosuppression (10.09 (8.89-11.46)) were vital signals when ibrutinib was combined with obinutuzumab, and pyrexia (4.22 (2.57-6.93)) had a high signal value when combined with lenalidomide. Hemorrhage had a lower signal value when combined with venetoclax compared to ibrutinib alone (2.50 (2.18-2.87) vs 3.60 (3.52-3.68))., Conclusions: The ibrutinib-obinutuzumab combo has the highest risk of infection, atrial fibrillation, and myelosuppression, and the ibrutinib-lenalidomide combo has the highest risk of pyrexia. However, the ibrutinib-venetoclax combo has a lower risk of hemorrhage than monotherapy.

Bruton tyrosine kinase (BTK) is a known drug target for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). In this study, a series of 1-amino-1H-imidazole-5-carboxamide derivatives with good inhibitory activity against BTK were selected to explore the structure-activity relationships of these BTK inhibitors (BTKIs). Furthermore, we concentrated on 182 prescriptions of Traditional Chinese Medicine with therapeutic effects on RA. 54 herbs with a frequency of ≥10 were counted to establish a database containing 4027 ingredients for virtual screening. Five compounds with relatively higher docking scores and better absorption, distribution, metabolism, elimination and toxicity (ADMET) parameters were then selected for higher precision docking. The results demonstrated that the potentially active molecules form hydrogen bond interactions with the hinge region residues Met477, Glu475, glycine-rich P-loop residue Val416, Lys430 and DFG motif Asp539. In particular, they also interact with the key residues Thr474 and Cys481 of BTK. The molecular dynamics (MD) results demonstrated that all five compounds above could bind with BTK stably as its cognate ligand in dynamic conditions. This work identified several potential BTKIs using a computer-aided drug design approach and may provide crucial information for developing novel BTKIs.Communicated by Ramaswamy H. Sarma.

This report summarizes a totality-of-evidence approach supporting recommendation of a 320-mg total daily dose, either as 160-mg twice daily (BID) or 320-mg once daily (QD) for zanubrutinib in patients with mantle cell lymphoma. Data were derived from a phase 2 study in patients receiving 160-mg BID and a phase 1/2 study with similar response rates observed with 160-mg BID or 320-mg QD. Given the limited number of patients in the QD dose group, population pharmacokinetics and exposure-response analyses were employed to bridge the two regimens. The analyses showed that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety endpoints. The totality of data, including pharmacokinetic, pharmacodynamic, safety, efficacy, and exposure-response analyses, provided support for the recommended 320-mg total daily dose for the approved indication.

Introduction: Waldenström's macroglobulinemia (WM) is a rare, incurable B-cell lymphoma, with a median survival of 5-10 years in symptomatic patients. There is no consensus on the standard of care and several agents are currently used in these patients. Areas covered: In this article, we will review the use of standard therapies and new drugs investigated such as monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, Bruton's tyrosine kinase inhibitors and novel agents in early-stage development. Expert commentary: RCD (Rituximab/Cyclophosphamide/Dexamethasone) is an effective and safe treatment in first line in WM. BR (Bendamustine/Rituximab) or BRD (Bortezomib/Rituximab/Dexamethasone) provide durable responses, and are still indicated in most patients. Ibrutinib is a new option and it was approved as primary therapy and for relapse. Carfilzomib based therapy represents an emerging option for proteasome-inhibitor based therapy for WM. Despite encouraging results, WM remains an incurable disease; therefore, new treatment options are needed. For this reason, continued participation in clinical trials should be encouraged.